Method for Preparing Indenoisoquinoline Derivatives

ABSTRACT

A method for preparing indenoisoquinoline derivatives represented by the following formula (I) is disclosed, which comprises the following steps: 
     
       
         
         
             
             
         
       
     
     (A) providing a first reactant represented by the following formula (II) and a second reactant represented by the following formula (III): 
     
       
         
         
             
             
         
       
     
     and 
     (B) reacting the first reactant represented by the formula (II) and the second reactant represented by the formula (III) in a solvent and selectively adding R 2 NH 2  therein, to obtain the indenoisoquinoline derivatives represented by the formula (I), wherein, R 1 , R 2 , R 3 , A, X, Y, Z, m and n are defined in the specification.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefits of the Taiwan Patent Application Serial Number 106137758, filed on Nov. 1, 2017, the subject matter of which is incorporated herein by reference.

BACKGROUND 1. Field

The present disclosure relates to a method for preparing indenoisoquinoline derivatives and, more particularly, to a method for preparing indenoisoquinoline derivatives with a simple process (even only comprising one step).

2. Description of Related Art

Indeno[1,2-c]isoquinoline derivatives have been reported to have potential inhibition activities against topoisomerase I. In fact, camptothecin (CPT) derivatives appear to be best topoisomerase I (Top1) inhibitors that are currently available. However, extensive research by Cushman and coworkers revealed that indenoisoquinoline derivatives are novel Top1 inhibitors with better pharmacokinetic features than CPT and that they have good chemical stability and resistance to reversal after the drug is removed. In addition, indenoisoquinoline derivatives showed potential activity for treating visceral leishmaniasis. Indeno[1,2-c]isoquinoline derivatives such as LMP-400 and LMP-776 have also been used as multi-tumor treatment drugs. Some important indenoisoquinoline derivatives have structures shown as follows.

Nowadays, many methods have been reported to synthesize indenoisoquinoline derivatives. For example, indenoisoquinoline derivatives can be prepared by the condensation of indeno[1,2-c]isochromene-5,11-diones and amines, phthalic anhydrides and arylmethanimines, and bromomethyl benzonitrile and homophthalic anhydrides. Benzamide and benzonitrile are starting materials to obtain indenoisoquinoline derivatives after coupling reaction. Benzamide derivatives are used to obtain indenoisoquinoline derivatives by Grubbs reaction and photocatalytic reaction. Or, terminal alkynes and arylmethylidene undergoes cycloaddition reaction with Co catalyst, followed by oxidization with SeO₂ to obtain indenoisoquinoline derivatives.

However, most of the reported methods have one or more shortcomings such as the need for multiple steps, limited substrate scope, un-available starting materials and other stereochemistry problems. Therefore, it is desirable to provide a method for preparing indenoisoquinoline derivatives with a simple process (even only comprising one step), which can bring great benefits to the syntheses of clinical used indenoisoquinoline derivatives.

SUMMARY

The present disclosure is to provide a method for preparing indenoisoquinoline derivatives, wherein the indenoisoquinoline derivatives can be rapidly synthesized with a simple process by using the method of the present disclosure.

The present disclosure provides a method for preparing indenoisoquinoline derivatives represented by the following formula (I), which comprises the following steps:

-   -   (A) providing a first reactant represented by the following         formula (II) and a second reactant represented by the following         formula (III):

-   -   wherein A is —OH or —NHR₂;     -   X is —CO—, —SO₂—, —CS—, —SO—, or substituted or unsubstituted         C₁₋₁₂ alkylene;     -   Y ring is substituted or unsubstituted C₆₋₁₄ aryl, or         substituted or unsubstituted C₄₋₁₈ heteroaryl;     -   Z is F, Cl, Br or I;     -   n is an integral of 1 to 4;     -   each R₁ independently is H, nitro, halogen, or substituted or         unsubstituted C₁₋₁₂ alkoxy; or when n is 2, two adjacent R₁ and         carbon atoms attached thereto together form a substituted or         unsubstituted C₃₋₁₈ alkylene oxide;     -   and     -   R₂ is H, substituted or unsubstituted C₁₋₁₂ alkyl, substituted         or unsubstituted C₂₋₁₂ alkenyl, substituted or unsubstituted         C₃₋₁₈ cycloalkyl, substituted or unsubstituted C₃₋₁₈         cycloalkenyl, substituted or unsubstituted C₄₋₁₈         heterocycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl, or         substituted or unsubstituted C₄₋₁₈ heteroaryl,

-   -   wherein m is an integral of 1 to 4; and     -   each R₃ independently is H, halogen, nitro, substituted or         unsubstituted C₁₋₁₂ alkoxy; or when m is 2, two adjacent R₃ and         carbon atoms attached thereto together form a substituted or         unsubstituted C₃₋₁₈ alkylene oxide;     -   and     -   (B) reacting the first reactant represented by the formula (II)         and the second reactant represented by the formula (III) in a         solvent and selectively adding R₂NH₂ therein, to obtain the         indenoisoquinoline derivatives represented by the formula (1).

Although various methods for preparing indenoisoquinoline derivatives have been reported, most of the reported methods have one or more shortcomings such as the need for multiple steps, limited substrate scope, un-available starting materials and other stereochemistry problems. In the method of the present disclosure, iodobenzene derivatives comprising lactam (X=—CO—), sulphonamide (X=—SO₂—), thioamide (X=CS), sulfinamide (X=SO) or alkylamine (X=alkyl) are used as a starting material, and reacted with indandione derivatives to obtain indenoisoquinoline derivatives rapidly and effectively. In some aspects of the present disclosure, the indenoisoquinoline derivatives even can be obtained with single step. In addition, in the method of the present disclosure, almost all the iodobenzene derivatives and the indandione derivatives are commercially available, and the problem of un-available starting materials can be prevented.

In the method of the present disclosure, the used solvent can be water, MeCN, DMF, DMSO, dioxane, toluene, or a combination thereof. In one embodiment of the present disclosure, the solvent is water. In another embodiment of the present disclosure, the solvent is MeCN.

In the method of the present disclosure, a catalyst can be further added in the step (B), wherein the catalyst comprises Cu⁺ or Cu²⁺. The catalyst can be selected from the group consisting of CuI, CuSO₄, CuCl, CuCl₂, and a hydrate thereof, but the present disclosure is not limited thereto. In one embodiment of the present disclosure, the catalyst is CuCl₂. In another embodiment of the present disclosure, the catalyst is CuSO₄.

In the method of the present disclosure, an alkali may be further added in the step (B), wherein the alkali can be a salt which comprises an alkaline metal. The alkali can be selected from the group consisting of K₂CO₃, Na₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, CsOH, Li₃PO₄, Na₃PO₄, K₃PO₄ and Cs₃PO₄, but the present disclosure is not limited thereto. In one embodiment of the present disclosure, the alkali is Cs₂CO₃.

In one embodiment of the present disclosure, in the step (B), the used solvent is MeCO, the used catalyst is CuCl₂, and the used alkali is Cs₂CO₃. In another embodiment of the present disclosure, in the step (B), the used solvent is water, the used catalyst is CuCl₂, and the used alkali is Cs₂CO₃. However, the present disclosure is not limited thereto.

In the method of the present disclosure, the temperature in the step (B) is not particularly limited, and can be adjusted according to the used solvent and reactor. For example, the temperature can be ranged from 70° C. to 150° C., or from 80° C. to 130° C. The reactor used in the step (B) is also not particularly limited. For example, the reaction can be performed with heat at room temperature and atmosphere in an opening system, the reaction can be performed with heat by using a micro-reactor, or the reaction can be performed by using a high pressure system. However, the present disclosure is not limited thereto.

In the method of the present disclosure, X in the formulas (I) and (II) can be —CO—, —SO₂—, —CS—, —SO—, or substituted or unsubstituted C₁₋₁₂ alkylene. In one embodiment of the present disclosure, X is —CO— or —SO₂—.

In the method of the present disclosure, R₂ can be H, substituted or unsubstituted C₁₋₁₂ alkyl, substituted or unsubstituted C₂₋₁₂ alkenyl, substituted or unsubstituted C₃₋₁₈ cycloalkyl, substituted or unsubstituted C₃₋₁₈ cycloalkenyl, substituted or unsubstituted C₄₋₁₈ heterocycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl, or substituted or unsubstituted C₄₋₁₈ heteroaryl. In one embodiment of the present disclosure, R₂ is H, methyl, ethyl, propyl, butyl, allyl, phenyl, benzyl, morpholinoethyl, morpholinopropyl, imidazolethyl, imidazolpropyl, methoxyethyl, methoxypropyl, methoxybutyl, phenylethyl, phenylpropyl, phenylbutyl, fluorophenyl, chlorophenyl,

wherein * is a bonding position.

In the method of the present disclosure, Z in the formula (II) can be F, Cl, Br or I. In one embodiment of the present disclosure, Z is I.

In one embodiment of the present disclosure, the formula (II) can be one of the following formulas (II-1) to (II-3):

wherein Y₁ is C, N or S.

In one embodiment of the present disclosure, the formula (II) is one of the following formulas (II-4) to (II-8):

wherein, in the formulas (II-5) to (II-7), R₁ is nitro, Br, Cl, methoxy, ethoxy, propoxy or butoxy; or in the formula (II-6), two adjacent R₁ and carbon atoms attached thereto together form a dioxolane.

In one embodiment of the present disclosure, the formula (III) can be one of the following formulas (III-1) to (III-4):

wherein, in the formulas (III-2) to (III-4), R₃ is Br, nitro, substituted or unsubstituted C₁₋₁₂ alkoxy; or in the formulas (III-2), two adjacent R₃ and carbon atoms attached thereto together form a substituted or unsubstituted C₃₋₁₈ alkylene oxide. In another embodiment of the present disclosure, in the formulas (III-2) to (III-4), R₃ is methoxy, ethoxy or propoxy; or in the formula (III-2), two adjacent R₃ and carbon atoms attached thereto together form dioxolane.

In one embodiment of the present disclosure, when A is —NHR₂, R₂NH₂ is not added into the reaction in the step (B).

In another embodiment of the present disclosure, when A is —OH, the step (B) may further comprise the following steps: (B1) reacting the first reactant represented by the formula (II) and the second reactant represented by the formula (III) in the solvent to obtain an intermediate represented by the following formula (IV):

and (B2) reacting the intermediate represented by the formula (IV) with R₂NH₂ to obtain the indenoisoquinoline derivatives represented by the formula (I).

In the step (B1), a catalyst can be further added into the reaction, wherein the catalyst comprises Cu⁺ or Cu²⁺. The catalyst can be selected from the group consisting of CuI, CuSO₄, CuCl, CuCl₂, and a hydrate thereof, but the present disclosure is not limited thereto. In one embodiment of the present disclosure, the catalyst is CuCl₂. In another embodiment of the present disclosure, the catalyst is CuSO₄.

In addition, in the step (B1), an alkali is further added into the reaction, wherein the alkali can be a salt which comprises an alkaline metal. The alkali can be selected from the group consisting of K₂CO₃, Na₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, CsOH, Li₃PO₄, Na₃PO₄, K₃PO₄ and Cs₃PO₄, but the present disclosure is not limited thereto. In one embodiment of the present disclosure, the used alkali is Cs₂CO₃.

Furthermore, in the step (B2), an acid can be further added into the reaction. By the addition of the acid, the intermediate represented by the formula (IV) and R₂NH₂ can be reacted under an acidic environment. Herein, the pH in the step (B2) can be ranged from 1 to 5, or from 1 to 3. The used amount of the acid can be ranged from 3 equivalent to 5 equivalent. An example of the acid can be camphorsulfonic acid (CSA), but the present disclosure is not limited thereto.

In one embodiment of the present disclosure, the formula (I) can be one of the following formulas (I-1) to (I-9):

-   -   wherein Y₁ is C, N or S; and     -   in the formulas (I-2) to (I-5), (I-7) and (I-9), R₃ is         substituted or unsubstituted C₁₋₁₂ alkoxy; or in the formulas         (I-2), (I-7) and (I-9), two adjacent R₃ and carbon atoms         attached thereto together form a substituted or unsubstituted         C₃₋₁₈ alkylene oxide.

In one embodiment of the present dislcousre, the formula (I) can be one of the following formulas (I-10) to (I-20);

-   -   wherein, in the formulas (I-11), (I-12), (I-17), (I-18) and         (I-19), R₁ is nitro, Br, Cl, methoxy, ethoxy, propoxy or butoxy;         or in the formulas (I-12) and (I-18), two adjacent R₁ and carbon         atoms attached thereto together form dioxolane; and     -   in the formulas (I-13) to (I-18), R₃ is methoxy, ethoxy or         propoxy; or in the formulas (I-13), (I-17) and (I-18), two         adjacent R₃ and carbon atoms attached thereto together form         dioxolane.

In one embodiment of the present disclosure, the formula (I) can be one of the following formulas (1) to (46):

In the method of the present dislcosure, alkyl(ene), alkoxy, alkenyl, cycloalkyl, cycloalkenyl, alkylene oxide, heterocycloalkyl, aryl, and heteroaryl present in the compounds include both substituted and unsubstituted moieties, unless specified otherwise. Possible substituents include, but are not limited to, alkyl, cycloalkyl, halogen, alkoxy, alkenyl, heterocycloalkyl, aryl, heteroaryl, ester, amino or carboxyl; but alkyl cannot be substituted with alkyl.

In the present disclosure, the term “halogen” includes F, Cl, Br and I.

In the present disclosure, the term “alkyl(ene)” refers to linear and branched alkyl, and includes, for example, linear or branched C₁₋₁₂ alkyl(ene), C₁₋₈ alkyl(ene) or C₁₋₆ alkyl(ene). Specific examples of alkyl(ene) include, but are not limited to, methyl(ene), ethyl(ene), n-propyl(ene), iso-propyl(ene), n-butyl(ene), sec-butyl(ene), iso-butyl(ene), tert-butyl(ene), pentyl(ene), neo-pentyl(ene) or hexyl(ene).

In the present disclosure, the term “alkoxy” refers to a moiety that the alkyl defined in the present disclosure coupled with an oxygen atom, and includes, for example, linear or branched C₁₋₁₂ alkoxy, C₁₋₈ alkoxy or C₁₋₆ alkoxy. Specific examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, neo-pentyloxy or hexyloxy.

In the present disclosure, the term “alkenyl” includes linear or branch hydrocarbon groups with at least one double bond, and includes, for example, linear or branch C₂₋₁₂ hydrocarbon groups with at least one double bond, linear or branch C₂₋₈ hydrocarbon groups with at least one double bond, or linear or branch C₂₋₆ hydrocarbon groups with at least one double bond. Examples of the alkenyl include, but are not limited to vinyl, propenyl or butenyl.

In the present disclosure, the term “cycloalkyl” includes cyclic saturated hydrocarbon groups, which includes, for example, 3 to 18 carbon atoms (C₃₋₁₈), 3 to 12 carbon atoms (C₃₋₁₂) or 3 to 8 carbon atoms (C₃₋₈). Examples of the cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,4-cyclohexyl, cycleheptyl, cyclooctyl or adamantine.

In the present disclosure, the term “alkylene oxide” refers to a moiety that the cycloalkyl defined in the present disclosure coupled with at least one oxygen atom, and includes, for example, 3 to 18 carbon atoms (C₃₋₁₈), 3 to 12 carbon atoms (C₃₋₁₂) or 3 to 8 carbon atoms (C₃₋₈) as well as one or two oxygen atoms. Examples of the alkylene oxide include, but are not limited to, dioxolane.

In the present disclosure, the term “cycloalkenyl” includes cyclic unsaturated hydrocarbon groups, which includes 3 to 18 carbon atoms (C₃₋₁₈), 3 to 12 carbon atoms (C₃₋₁₂) or 3 to 8 carbon atoms (C₃₋₈). Examples of the cycloalkenyl include, but are not limited to cyclopentenyl, cyclohexenyl or cycloheptenyl.

In the present disclosure, the term “heterocycloalkyl” refers to a moiety that at least one carbon atom in the cycloalkyl defined in the present disclosure is substituted with at least one hetero atom, wherein each hetero atom is selected from O, S and N. Examples of the heterocycloalkyl include, but are not limited to tetrahydrofurfuryl.

In the present disclosure, the term “aryl” includes 6-membered single aromatic ring, 10-membered double aromatic ring or 14-membered triple aromatic ring. Examples of the aryl include, but are not limited to phenyl, naphthyl, pyrenyl, anthryl or phenanthryl.

In the present disclosure, the term “heteroaryl” refers to an aromatic ring having 5-8 membered single ring, 8-12 membered double ring or 11-14 membered triple ring and at least one hetero atom, in which each hetero atom in the ring is selected from O, S and N. Examples of the heteroaryl include, but are not limited to pyridyl, pyrimidinyl, furyl, thiazolyl, imidazolyl, or thienyl

Other novel features of the disclosure will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings.

DETAILED DESCRIPTION OF EMBODIMENT

The following embodiments when read with the accompanying drawings are made to clearly exhibit the above-mentioned and other technical contents, features and/or effects of the present disclosure. Through the exposition by means of the specific embodiments, people would further understand the technical means and effects the present disclosure adopts to achieve the above-indicated objectives. Moreover, as the contents disclosed herein should be readily understood and can be implemented by a person skilled in the art, all equivalent changes or modifications which do not depart from the concept of the present disclosure should be encompassed by the appended claims.

Analysis Instrument NMR Spectroscopy

¹H-NMR spectra were obtained with Bruker Avance 400 or Bruker Avance III HD 400 spectrometer system. The sample solvent was chloroform-d¹ (CDCl₃) or dimethylsulfoxide-d⁶ (DMSO-d₆). Chemical shifts (δ) are reported in parts per million. For ¹H-NMR spectrum, H absorption peak of the remaining chloroform in CDCl₃ is used as an internal standard, δ=7.26 ppm. The definition of the splitting pattern of the ¹H-NMR spectrum is: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; and m, multiplet. The coupling constant is presented by J in Hz. The data of the spectrum are sequentially illustrated by: chemical shift (splitting pattern, coupling constant and number of protons). ¹³C-NMR spectra were obtained with the same instruments, C absorption peak of the remaining chloroform in CDCl₃ is used as an internal standard, δ=77.23 ppm.

Thin Layer Chromatography (TLC)

The sample was spread with Merck silica gel 60 F₂₅₄ Al TLC plate, and observed the TLC plate with an UV light or a developer.

Column Chromatography

Merck Geduran® Si 60 (230-400 mesh) was used in the flash column chromatography, and samples were separated according to Still manual.

High Resolution Mass Spectrometry (HRMS)

Finnigan MAT 95S, Finnigan MAT-95XL or Finnigan/Thermo Quest MAT mass spectrometry was used, and the data are recorded by mass/charge (m/z).

Melting Point (mp)

Samples were placed in capillaries, and the melting points of the samples were measured with Mel-Temp melting point apparatus, which was not calibrated.

Reagents

Unless specified otherwise, reagents, solvents and drying agents used in the following experiments are purchased from Merck, TCI, Acros, Aldrich, Show or Lancaster without further purification. The D-containing solvent for NMR spectroscopy was purchased from Merck and Aldrich.

In addition, the eluent and the solvent, such as dichloromethane, chloroform, ethyl acetate, n-hexane and methanol, are ACS grade or obtained from purification by distillation using industrial grade solvent.

Most of the starting materials 2-iodobenzamide derivatives and 1,3-indandione derivatives are commercially available. In addition, 2-iodobenzamide derivatives were obtained from 2-iodobenzoic acid following publications ((a) A. M. Suess, M. Z. Ertem, C. J. Cramer, S. S. Stahl, JACS 2013, 135, 9797-9804. (b) N. Zhang, B. Li, H. Zhong, J. Huang, Org. Biomol. Chem. 2012, 10, 9429-9439.). Furthermore, 1,3-indandione derivatives were also obtained from benzaldehyde following publications ((a) Sterling Winthrop Inc., Patent: U.S. Pat. No. 5,554,620, A1, 1996. (b) G. Tóth, K. E. Kövér, Synth. Commun. 1995, 25, 3067-3074. (c) J. D. Enas, J. G. Garcia, C. A. Mathis, J. M. Gerdes, J. Fluorine Chem. 1993, 63, 233-241. 5,6-Methylenedioxyindandione 2c was prepared according to the following papers: (d) P. V. R. Acharyulu, P. K. Dubey, P. V. V. P. Reddy, T. Suresh, Synth. Commun. 2009, 39, 3217-3231. (e) Ube Industries, Ltd., Patent: EP1621529 A1, 2006. (f) Schering Corporation, Patent: WO200448322 A1, 2004. (g) P. Dallemagne, S. Rault, J. C. Pilo, M. P. Foloppe, M. Robba, Tetrahedron Lett. 1991, 32, 6327-6328. (h) H. E. Zimmerman, M.-L. Viriot-Villaume, J. Am. Chem. Soc. 1973, 95, 1274-1280. 5-bromoindandione 2d was prepared according to the following papers: (i) Tso, S.-C.; Lou, M.; Wu, C.-Y.; Gui, W.-J.; Cuang, J. L.; Morlock, L. K.; Williams, N. S.; Wynn, R. M.; Qi, X.; Chuang, D. T. J. Med. Chem. 2017, 60, 1142-1150. Peloton Therapeutics Inc., Patent: 201535223 A1, 2015.)

The process for preparing 2-iodobenzamide derivatives and 1,3-indandione derivatives are illustrated in the following Scheme I.

Embodiment 1

The process for preparing Compound (1) is illustrated in the following Scheme II.

Preparation With Organic Solvent

2-Iodobenzamide 1a (0.261 g, 1 mmol), 1,3-indandione 2a (0.219 g, 1.5 mmol) and Cs₂CO₃ (0.39 g, 1.2 mmol) were added to a 50 mL round bottom flask equipped with a magnetic stir bar and added 10-15 mL of acetonitrile. The mixture was heated to 90° C. for 5 min and then added CuCl₂ (0.0085 g, 0.05 mmol) and reacted for the time indicated. The progress of the reaction was monitored by TLC for disappearance of 2-Iodobenzamide 1a. After the reaction was completed, it was brought back to r.t. and added 1-2 mL of brine, the acetonitrile was removed under reduced pressure. More iced brine was added to solidify the product, the product was filtered by gravity filtration and then washed thoroughly with iced water to yield the pure Compound (1) (199 mg, 76%).

Preparation With Aqueous Solvent

2-Iodobenzamide 1a (0.261 g, 1 mmol), 1,3-indandione 2a (0.161 g, 1.1 mmol), Cs₂CO₃ (0.39 g, 1.2 mmol) and CuSO₄.5H₂O (1.25 mg, 5 μmol) were placed in 100 mL high pressure tube, and then 5 mL water was added therein, followed by sealing the tube. The reaction was heated and rapidly stirred in an oil bath, which is pre-heated to 130° C. The progress of the reaction was monitored by TLC. After the reaction was completed, it was brought back to r.t., and separated by a centrifugation. The product was washed with water. The centrifuge tube was placed in an oven to dry the product to yield the pure Compound (1) (214 mg, 82%).

Embodiments 2-31

The preparations of Compounds (2) to (31) were followed the preparation process using an organic solvent or an aqueous solvent of Embodiment 1. Herein, in the preparation process using the organic solvent, if the crude was sticky oil after removing acetonitrile, adding moderate amount of acetone or EA was acceptable to assist solidification of the product.

Embodiment 32

The process for preparing Compound (32) is illustrated in the following Scheme III. The process for preparing the indenoisoquinoline derivative with an organic solvent was similar to that illustrated in Embodiment 1, and is not repeated again.

Embodiment 33

The process for preparing Compound (33) is illustrated in the following Scheme IV. The process for preparing the indenoisoquinoline derivative with an organic solvent was similar to that illustrated in Embodiment 1, and is not repeated again.

Embodiment 34

The process for preparing Compound (34) is illustrated in the following Scheme V. The process for preparing the indenoisoquinoline derivative with an organic solvent was similar to that illustrated in Embodiment 1, and is not repeated again.

Compound (34) was further proceeded with Heck reaction and reductive cyclization to obtain multi-ring compound (4a). Compound (34) (0.116 g, 0.25 mmol), PdCl₂(PPh₃)₂ (0.009 g ,0.0125 μmol) and NaOAc (0.041 g, 0.5 mmol) were added to a 10 mL round-bottom flask under N₂ atmosphere, then added 4 mL of DMA and heated to 120° C. for 16 h. After the reaction was completed, the mixture was purified by column chromatography using EA/Hexane as the eluent to yield the pure product (4a) as red solid (0.035 g, 42%).

Embodiment 35

The process for preparing Compound (35) is illustrated in the following Scheme VI. The process for preparing the indenoisoquinoline derivative with an organic solvent was similar to that illustrated in Embodiment 1, and is not repeated again.

Compound (35) was further proceeded with Heck reaction and reductive cyclization to obtain multi-ring compound (5a). A mixture of Compound (35) (0.092 g, 0.25 mmol), Fe powder (0.07 g, 1.25 mmol) and AcOH (4 mL) were heated to 80° C. for 2 h. After the reaction was completed, the mixture was filtered through celite pad and wash with EA. The eluent was evaporated and the solid collected was then washed with EA to yield the desired product (5a) as red solid (0.066 g, 83%).

Embodiments 36-39

The processes for preparing Compounds (36) to (39) were similar to the process for preparing the indenoisoquinoline derivative with an aqueous solvent illustrated in Embodiment 1, and is not repeated again.

Embodiment 40

The process for preparing Compound (40) is illustrated in the following Scheme VII.

N-methyl-2-iodobenzene sulfonamide (0.297 g, 1 mmol), 1,3-indandione (0.160 g, 1.1 mmol) and Cs₂CO₃ (0.391 g, 1.2 mmol) were placed in 50 mL high pressure tube, and then 4 mL water was added therein, followed by sealing the tube. The reaction was heated to 100° C. and reacted for 2 hr. After the reaction was brought back to r.t., 4 mL water was added to dilute the reaction. Under severe stirring, 1M p-toluene sulfonic acid aqueous solution (5 mL) was slowly added, slowly heated to 50° C. and reacted for 1 day. The progress of the reaction was monitored by TLC. After the reaction was completed, the product was separated by a centrifugation, and sequentially washed by water and saturated NaHCO₃ aqueous solution. The centrifuge tube was placed in an oven (60° C.) to dry the product to yield the pure Compound (40) (137 mg, 46%).

The names, reaction times (time), product weights (weight), yields, appearances (appear.) and melting points (mp.) of Compounds (1) to (40), (4a) and (5a) are listed in the following Tables 1 and 2. Table 1 shows the data in which the reaction was performed with an organic solvent, and Table 2 shows the data in which the reaction was performed with an aqueous solvent.

TABLE 1 Reaction using organic solvent Weight Time Yield Mp. Formula Name (mg) (hr) (%) Appear. (° C.) (1)

6-methyl-5H-indeno[1,2- c]isoquinoline-5,11(6H)- dione 199 3 76 Red Solid 240-242 (2)

5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 138 5 56 Orange Solid >350 (3)

5-ethyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 177 3 64 Brown Solid 184-186 (4)

6-allyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 187 8 65 Red Solid 160-162 (5)

6-benzyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 202 3 61 Orange Solid 208-210 (6)

6-phenyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 220 2.5 68 Red Solid 242-244 (7)

6-(2-morpholinoethyl)-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 224 2.5 62 Pale brown Solid 192-194 (8)

6-(2-methoxyethyl)-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 199 2.5 65 Red Solid 184-186 (9)

6-methyl-3-nitro-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 261 1 85 Red Solid >350 (10)

3-bromo-6-methyl-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 201 4 59 Orange Solid 272-274 (11)

6-benzyl-3-chloro-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 249 6 67 Orange Solid 261-263 (12)

3-methoxy-6-methyl-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 187 5 64 Brown Solid 228-230 (13)

2,3-dimethoxy-6-methyl- 5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 171 6 53 Red Solid 281-283 (14)

6-benzyl-2,3-dimethoxy- 5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 243 3 61 Brown Solid 289-290 (15)

6-methyl-5H-[1,3]dioxolo [4,5-g]indeno[1,2-c] isoquinoline-5,11(6H)-dione 220 4 72 Red Solid 327-329 (16)

6-benzyl-5H-[1,3]dioxolo [4,5-g]indeno[1,2-c] isoquinoline-5,11(6H)-dione 256 16 67 Brown Solid 302-304 (17)

8,9-dimethoxy-6-methyl- 5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 206 3.5 64 Brown Solid 326-328 (18)

6-benzyl-8,9-dimethoxy- 5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 274 4.5 69 Brown Solid 272-274 (19)

8,9-dimethoxy-6-methyl- 3-nitro-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 268 1 73 Brown Solid 345-347 (D) (20)

3-bromo-8,9-dimethoxy- 6-methyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 251 2 63 Brown Solid >350 (21)

8,9-dimethoxy-6-methyl- 5H-[1,3]dioxolo[4,5-g]indeno [1,2-c]isoquinoline-5,11 (6H)-dione 223 4 61 Brown Solid 321-323 (22)

6-benzyl-8,9-dimethoxy- 5H-[1,3]dioxolo[4,5-g] indeno[1,2-c]isoquinoline- 5,11(6H)-dione 287 16 65 Brown Solid 315-317 (23)

6-methyl-5H-[1,3]dioxolo [4′,5′:5,6]indeno[1,2-c] isoquinoline-5,1(6H)-dione 202 3 66 Brown Solid 308-310 (24)

6-benzyl-5H-[1,3]dioxolo [4′,5′:5,6]indeno[1,2-c] isoquinoline-5,12(6H)-dione 229 5 60 Brown Solid 297-299 (25)

6-allyl-5H-[1,3]dioxolo [4′,5′:5,6]indeno[1,2-c] isoquinoline-5,12(6H)-dione 249 4 75 Brown Solid 242-244 (26)

6-(2-methoxyethyl)-5H- [1,3]dioxolo[4′,5′:5,6] indeno[1,2-c]isoquinoline- 5,12(6H)-dione 186 1.5 53 Brown Solid 205-207 (D) (27)

3-bromo-6-methyl-5H- [1,3]dioxolo[4′,5′:5,6]indeno [1,2-c]isoquinoline-5,12 (6H)-dione 238 2.5 62 Brown Solid 322-324 (D) (28)

3-methoxy-6-methyl-5H- [1,3]dioxolo[4′,5′:5,6]indeno [1,2-c]isoquinoline-5,12 (6H)-dione 218 5 65 Brown Solid 286-288 (29)

2,3-dimethoxy-6-methyl- 5H-[1,3]dioxolo[4′,5′:5,6] indeno[1,2-c]isoquinoline- 5,12(6H)-dione 201 10 55 Brown Solid 298-300 (D) (30)

2,3-dimethoxy-6-(3- morpholinopropyl)-5H-[1,3] dioxolo[4′,5′:5,6]indeno[1,2-c] isoquinoline-5,12(6H)-dione 259 18 54 Brown Solid 293-295 (31)

6-(3-(1H-imidazol-1-yl) propyl)-2,3-dimethoxy-5H- [1,3]dioxolo[4′,5′:5,6] indeno[1,2-c]isoquinoline- 5,12(6H)-dione 225 18 49 Brown Solid 320-322 (32)

11-methyl-5-phenyl-5H- benzo[b]indeno[1,2-h][1,6] naphthyridine-6,13-dione 311 12 80 Pale brown Solid >350 (33)

5-benzyl-4H-indeno[1,2-b] thieno[2,3-d]pyridine-4,10- (5H)-dione 172 20 50 Orange Solid 232-234 (34)

6-(2-iodobenzyl)-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 445 2.5 96 Orange Solid 236-238 (35)

6-(2-nitrophenyl)-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 258 0.5 70 Pale brown Solid 286-288 (4a)

1H-6a-azabenzo-[a]benzo [5,6]cyclohepta[1,2,3,4-def] fluorene-1,6-(7H)-dione 141 — 42 Red Solid 276-278 (5a)

10H-benzo[4,5]imidazo[2,1-a] indeno[1,2-c]isoquinoline- 10-one 267 — 83 Red Solid 286-288 **(D): Decomposed

TABLE 2 Reaction using aqueous solvent Weight Time Yield Mp. Formula Name (mg) (hr) (%) Appear. (° C.) (1)

6-methyl-5H-indeno[1,2- c]isoquinoline-5,11(6H)- dione 219 1 84 Red Solid 240-244 (2)

5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 185 0.75 82 Orange Solid >350 (4)

6-allyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 230 1 80 Red Solid 160-162 (5)

6-benzyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 256 0.75 76 Orange Solid 208-210 (6)

6-phenyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 268 0.7 83 Red Solid 242-244 (9)

6-methyl-3-nitro-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 288 0.3 94 Red Solid >350 (10)

3-bromo-6-methyl-5H-indeno [1,2-c]isoquinoline-5,11 (6H)-dione 208 0.75 61 Orange Solid 272-274 (12)

3-methoxy-6-methyl-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 224 1 77 Brown Solid 228-230 (13)

2,3-dimethoxy-6-methyl- 5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 289 1 90 Red Solid 281-283 (15)

6-methyl-5H-[1,3]dioxolo [4,5-g]indeno[1,2-c] isoquinoline-5,11(6H)-dione 266 0.75 87 Red Solid 327-329 (17)

8,9-dimethoxy-6-methyl- 5H-indeno[1,2-c]isoquinoline- 5,11(6H)-dione 199 1 62 Brown Solid 326-328 (20)

3-bromo-8,9-dimethoxy- 6-methyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 288 0.75 72 Brown Solid >350 (23)

6-methyl-5H-[1,3]dioxolo [4′,5′:5,6]indeno[1,2-c] isoquinoline-5,1(6H)-dione 211 0.75 83 Brown Solid 308-310 (26)

6-(2-methoxyethyl)-5H- [1,3]dioxolo[4′,5′:5,6] indeno[1,2-c]isoquinoline- 5,12(6H)-dione 234 0.5 67 Brown Solid 205-207 (D) (28)

3-methoxy-6-methyl-5H- [1,3]dioxolo[4′,5′:5,6]indeno [1,2-c]isoquinoline-5,12 (6H)-dione 241 1 72 Brown Solid 286-288 (30)

2,3-dimethoxy-6-(3- morpholinopropyl)-5H-[1,3] dioxolo[4′,5′:5,6]indeno[1,2-c] isoquinoline-5,12(6H)-dione 244 2.5 51 Brown Solid 293-295 (31)

6-(3-(1H-imidazol-1-yl) propyl)-2,3-dimethoxy-5H- [1,3]dioxolo[4′,5′:5,6] indeno[1,2-c]isoquinoline- 5,12(6H)-dione 349 3 76 Brown Solid 320-322 (36)

8,9-dimethoxy-6-phenyl- 5H-indeno-[1,2-c] isoquinoline-5,11(6H)-dione 318 0.75 83 Brown Solid 225-226 (37)

8-bromo-6-methyl-5H- indeno-[1,2-c]isoquinoline- 5,11(6H)-dione 82 4 24 Red Solid 267-268 (38)

9-bromo-6-methyl-5H- indeno-[1,2-c]isoquinoline- 5,11(6H)-dione 82 4 24 Red Solid 274-275 (39)

6-methyl-7-nitro-5H-indeno- [1,2-c]isoquinoline-5,11 (6H)-dione 86 6 28 Brown Solid 289-290 (40)

6-methylbenzo[e]indeno [1,2-c][1,2]thiazin-11(6H)- one 5,5-dioxide 137 — 46 Red Solid 210-212 **(D): Decomposed

Embodiment 41

In the present embodiment, Compound (6) was prepared according to the following Scheme VIII.

This reaction was an one-pot reaction. 2-iodobenzoic acid (0.5 mmol), 1,3-indandione (0.6 mmol), CuSO₄.5H₂O (1 mmol) and Cs₂CO₃ (0.75 mmol) were added into a reaction bottle, followed by adding water (2 mL). The reaction was performed at 100° C. for 2 hr, and an intermediate was obtained (83%). After the first step was completed, it was brought back to r.t. to proceed the second step. Then, aniline (1.5 eq.) was added into the reaction bottle, followed by slowly adding CSA aqueous solution (4 eq.). After the addition was completed, pH stripes were used to confirm whether the pH value of the reaction was reached to 1. Then, the reaction was heated to 100° C. After 12 hr, Compound (6) was obtained.

Embodiments 42-48

The preparations of Compounds (5), (26), (42) to (46) were similar to Scheme VIII shown in Embodiment 41, and only the amounts of the reactants and the reaction times were adjusted.

The names, reaction times (time), product weights (weight), yields, appearances (appear.) and melting points (mp.) of Compounds (5), (6), (26), (42) to (46) prepared in Embodiments 41 to 48 are listed in the following Table 3.

TABLE 3 Time for 2^(nd) Weight step Yield Mp. Formula Name (mg) (hr) (%) Appear. (° C.) (5)

6-benzyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 256 12 70 Orange Solid 208-210 (6)

6-phenyl-5H-indeno[1,2-c] isoquinoline-5,11(6H)-dione 268 12 90 Red Solid 242-244 (26)

6-(2-methoxyethyl)-5H- [1,3]dioxolo[4′,5′:5,6] indeno[1,2-c]isoquinoline- 5,12(6H)-dione 186 12 60 Brown Solid 205-207 (D) (42)

6-(4-fluorophenyl)-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 215 12 63 Orange Solid 277-278 (43)

6-(4-chlorophenyl)-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 240 12 67 Orange Solid 314-315 (44)

6-pentyl-indeno[1,2-c] isoquinoline-5,11(6H)-dione 200 24 63 Red Solid 144-145 (45)

6-(4-phenylbutyl)-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 243 24 64 Orange Solid 139-140 (46)

6-(3-methoxypropyl)-5H- indeno[1,2-c]isoquinoline- 5,11(6H)-dione 166 12 52 Red Solid 158-160

NMR spectra and mass data of Compounds (1) to (46), (4a) and (5a) are listed as follows.

Compound (1): ¹H-NMR (400 MHz, CDCl₃) δ 8.69 (d, J=8.0 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.75-7.71 (m, 1H), 7.68-7.63 (m, 2H), 7.49-7.41 (m, 3H), 4.08 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.7, 163.7, 156.3, 137.9, 135.4, 134.1, 133.3, 132.4, 131.3, 128.8, 127.4, 123.7, 123.6, 123.5, 123.0, 108.6, 32.5; HRMS (ESI) m/z calcd for C₁₇H ₂NO₂ (M⁺+H) 262.0868, found 262.0869.

Compound (2): ¹H-NMR (400 MHz, (CD₃)₂SO) δ 8.39 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.87-7.73 (m, 2H), 7.54-7.41 (m, 4H); ¹³C-NMR (100 MHz, (CD₃)₂SO) δ 190.2, 164.6, 157.7, 137.6, 135.1, 134.1, 133.6, 131.8, 128.3, 126.7, 124.5, 122.9, 122.5, 121.2, 105.9; HRMS (ESI) m/z calcd for. C₁₆H₁₀NO₂ (M⁺+H) 248.0706, found 248.0705.

Compound (3): ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (d, J=8.1 Hz, 1H), 8.34 (d, J=8.1 Hz, 1H), 7.74-7.70 (m, 1H), 7.63 (d, J=6.7 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.48-7.38 (m, 3H), 4.60 (q, J=7.1 Hz, 2H), 1.55 (t, J=7.1 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.7, 163.5, 155.7, 137.3, 135.5, 134.0, 133.4, 132.5, 131.2, 128.6, 127.4, 123.8, 123.7, 123.5, 122.7, 108.8, 40.2, 14.7; HRMS (ESI) m/z calcd for C₁₈H₁₄NO₂ (M⁺+H) 276.1025, found 276.1026.

Compound (4): ¹H-NMR (600 MHz, CDCl₃) δ 8.68 (d, J=8.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.73-7.70 (m, 1H), 7.58 (d, J=6.2 Hz, 1H), 7.47-7.44 (m, 2H), 7.40-7.33 (m, 2H), 6.14-6.08 (m, 1H), 5.30 (d, J=10.4 Hz, 1H), 5.20-5.16 (m, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.7, 163.3, 156.0, 137.1, 135.3, 134.1, 133.3, 132.5, 131.6, 131.1, 128.8, 127.4, 123.7, 123.7, 123.3, 123.1, 117.6, 108.8, 46.6; HRMS (ESI) m/z calcd for C₁₉H₁₄NO₂ (M⁺+H) 288.1025, found 288.1024.

Compound (5): ¹H-NMR (400 MHz, CDCl₃) δ 8.76 (d, J=8.1 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 7.79-7.75 (m, 1H), 7.62-7.60 (d, J=6.8 Hz, 1H), 7.51-7.48 (m, 1H), 7.37-7.23 (m, 8H), 5.80 (s, 2H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 191.5, 164.7, 156.3, 137.0, 135.0, 134.9, 133.9, 132.8, 131.5, 129.4, 128.9, 128.1, 128.1, 125.9, 123.9, 123.4, 109.9, 48.9; HRMS (ESI) m/z calcd for C₂₃H₁₆NO₂ (M⁺+H) 338.1181, found 338.1183.

Compound (6): ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (d, J=7.9 Hz, 1H), 8.37 (d, J=8.1 Hz, 1H), 7.80 (m, 1H), 7.65-7.64 (m, 3H), 7.56-7.44 (m, 4H), 7.26-7.21 (m, 1H), 7.01-6.98 (m, 1H), 5.49 (d, J=7.5 Hz, 1H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.8, 163.8, 155.5, 137.7, 137.3, 135.0, 134.4, 132.9, 132.9, 130.9, 130.3, 128.9, 128.9, 127.5, 124.2, 123.9, 123.0, 122.6, 108.4; HRMS (ESI) m/z calcd for C₂₂H₁₄NO₂ (M⁺+H) 324.1025, found 324.1027.

Compound (7): ¹H-NMR (400 MHz, CDCl₃) δ 8.71 (d, J=8.2 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.49-7.44 (m, 2H), 7.42-7.39 (m, 1H), 4.69 (t, J=7.6 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 2.82 (t, J=7.6 Hz, 2H), 2.62 (t, J=4.6 Hz, 4H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.6, 163.5, 155.8, 137.4, 135.4, 134.1, 133.5, 132.5, 131.2, 128.6, 127.5, 123.7, 123.6, 123.5, 122.6, 108.9, 67.2, 56.9, 54.2, 42.6; HRMS (ESI) m/z calcd for C₂₂H₂₁N₂O₃ (M⁺+H) 361.1552, found 361.1553.

Compound (8): ¹H-NMR (600 MHz, CDCl₃) δ 8.70 (d, J=8.0 Hz, 1H), 8.33 (d, J=8.3 Hz, 1H), 7.73-7.70 (m, 2H), 7.61 (d, J=7.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.38-7.36 (m, 1H), 4.71 (t, J=6.4 Hz, 2H), 3.85 (t, J=6.4 Hz, 2H), 3.38 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.8, 163.8, 156.4, 137.7, 135.3, 134.1, 133.3, 132.6, 131.1, 128.6, 127.4, 123.8, 123.6, 123.5, 123.3, 108.9, 70.1, 59.5, 44.8; HRMS (ESI) m/z calcd for C₁₉H₁₆NO₃ (M⁺+H) 306.1130, found 306.1130.

Compound (9): ¹H-NMR (400 MHz, CDCl₃+CF₃CO₂D) δ 9.21 (s, 1H), 8.86 (d, J=8.9 Hz, 1H), 8.58 (d, J=8.9 Hz, 1H), 7.80 (d, J=7.1 Hz, 1H), 7.76 (d, J=7.1 Hz, 1H), 7.62-7.54 (m, 2H), 4.19 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃+CF₃CO₂D) δ 191.2, 163.9, 146.3, 137.0, 136.8, 135.0, 134.5, 133.0, 128.6, 125.3, 125.2, 124.8, 124.5, 123.0, 108.5, 33.5; HRMS (ESI) m/z calcd for C₁₇H₁₁N₂O₄ (M⁺+H) 307.0719, found 307.0716.

Compound (10): ¹H-NMR (400 MHz, CDCl₃) δ 8.56 (d, J=8.7 Hz, 1H), 8.50 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.68-7.64 (m, 2H), 7.46-7.40 (m, 2H), 4.07 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃+CF₃CO₂D) δ 191.7, 163.7, 156.4, 138.1, 137.3, 134.7, 134.3, 132.1, 131.3, 131.1, 125.4, 124.5, 124.4, 123.7, 122.0, 109.4, 33.4; HRMS (ESI) m/z calcd for C₁₇H₁₁BrNO₂ (M⁺+H) 339.9973, found 339.9970.

Compound (11): ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (d, J=8.5 Hz, 1H), 8.34 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.37-7.21 (m, 8H), 5.79 (s, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.5, 162.7, 156.3, 137.1, 135.3, 135.1, 134.8, 133.6, 131.3. 131.0, 129.4, 128.4, 128.0, 125.9, 125.5, 124.9, 123.6, 123.2, 108.6, 48.5; HRMS (ESI) m/z calcd for C₂₃H₁₅ClNO₂ (M++H) 372.0791, found 372.0789.

Compound (12): ¹H-NMR (400 MHz, CDCl₃) δ 8.59 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.64-7.55 (m, 2H), 7.41-7.33 (m, 3H), 4.06 (s, 3H), 3.93 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.8, 163.4, 159.2, 154.0, 138.3, 135.3, 133.3, 130.8, 126.5, 125.4, 125.1, 124.4, 123.5, 122.5, 109.0, 108.8, 55.8, 32.6; HRMS (ESI) m/z calcd for C₁₈H₁₄NO₃ (M⁺+H) 292.0974, found 292.0973.

Compound (13): ¹H-NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.70 (s, 1H), 7.62-7.58 (m, 2H), 7.43-7.34 (m, 2H), 4.07 (s, 3H), 4.05 (s, 3H), 4.00 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.9, 162.8, 155.1, 154.8, 149.7, 138.2, 135.4, 133.3, 130.9, 128.1, 123.4, 122.7, 117.9, 108.5, 103.7, 56.5, 56.3, 32.5; HRMS (ESI) m/z calcd for C₁₉H₁₆NO₄ (M⁺+H) 322.1079, found 22.1079.

Compound (14): ¹H-NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.73 (s, 1H), 7.56 (d, J=6.6 Hz, 1H), 7.37-7.33 (m, 2H), 7.28-7.22 (m, 6H), 5.79 (s, 2H), 4.09 (s, 3H), 3.99 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 191.1, 162.9, 155.3, 154.9, 149.8, 137.6, 135.8, 135.3, 133.4, 130.7, 129.3, 128.4, 127.8, 126.0, 123.2, 122.7, 118.0, 108.9, 108.7, 103.8, 56.6, 56.3, 48.3; HRMS (EST) m/z calcd for C₂₅H₂₀NO₄ (M⁺+H) 398.1392, found 398.1390.

Compound (15): ¹H-NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.69 (s, 1H), 7.63-7.60 (m, 2H), 7.44-7.35 (m, 2H), 6.10 (s, 2H), 4.04 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.8, 165.4, 159.2, 154.0, 138.3, 135.3, 133.3, 130.8, 126.5, 125.4, 125.1, 124.4, 123.5, 122.5, 109.0, 108.8, 55.8, 32.6; HRMS (ESI) m/z calcd for C₁₈H₁₂NO₄ (M⁺+H) 306.0766, found 306.0765.

Compound (16): ¹H-NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.70 (s, 1H), 7.57 (d, J=6.4 Hz, 1H), 7.35-7.33 (m, 2H), 7.26-7.21 (m, 6H), 6.11 (s, 2H), 5.76 (s, 2H); 13 C-NMR (100 MHz, CDCl₃) δ 190.8, 162.8, 154.9, 153.7, 148.3, 137.3, 135.7, 135.2, 133.5, 130.8, 130.2, 129.3, 128.3, 127.9, 125.9, 123.4, 122.8, 119.6, 109.1, 106.8, 102.2, 102.0, 48.3; HRMS (ESI) m/z calcd for C₂₄H₁₆NO₄ (M^(*)-1-H) 382.1079, found 382.1079.

Compound (17): ¹H-NMR (400 MHz, CDCl₃) δ 8.59 (d, J=8.0 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.42-7.39 (m, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 192.7, 156.1, 152.6, 151.2, 135.2, 132.8, 131.4, 128.6, 128.4, 127.8, 123.3, 122.5, 108.9, 108.8, 57.0, 56.7, 33.2; HRMS (ESI) m/z calcd for C₁₉H₁₆NO₄ (M⁺+H) 322.1079, found 322.1078.

Compound (18): ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (d, J=8.1 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 7.77-7.73 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.36 (m, 2H), 7.31 (d, J=7.1 Hz, 1H), 7.25 (d, J=7.5 Hz, 2H), 7.17 (s, 1H), 6.78 (s, 1H), 5.81 (s, 1H), 3.93 (s, 3H), 3.61 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ 190.6, 163.8, 156.3, 151.9, 150.6, 135.9, 134.1, 132.9, 130.3, 129.4, 128.9, 128.5, 127.9, 126.8, 125.5, 123.2, 123.0, 108.4, 108.0, 107.4, 56.5, 56.4, 48.2; HRMS (ESI) m/z calcd for C₂₅H₂₀NO₄ (M⁺+H) 398.1392, found 398.1391.

Compound (19): ¹H-NMR (500 MHz, CDCl₃+CF₃CO₂D) δ 9.11 (s, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.33 (s, 1H), 7.24 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 4.00 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ; 190.7, 163.7, 159.5, 152.8, 152.3, 145.7, 137.0, 130.1, 129.0, 128.5, 125.4, 124.6, 122.0, 109.2, 108.6, 107.6, 57.0, 56.8, 33.2; HRMS (ESI) m/z calcd for C₁₉H₁₅N₂O₆ (M⁺+H) 367.0930, found 367.0926.

Compound (20): ¹H-NMR (400 MHz, CDCl₃) δ 8.47-8.44 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 190.7, 163.0, 156.2, 152.4, 151.3, 137.5, 131.1, 128.4, 124.8, 123.7, 120.8, 108.5, 108.1, 107.8, 56.9, 56.6, 32.8; HRMS (ESI) m/z calcd for C₁₉H₁₄BrNO₄ (M⁺+H) 399.0106, found 399.0109.

Compound (21): ¹H-NMR (500 MHz, CDCl₃) δ 8.03 (s, 1H), 7.66 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 6.08 (s, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃+CF₃CO₂D) δ 193.1, 155.2, 153.8, 152.8, 150.8, 149.2, 131.8, 131.4, 128.2, 125.2, 109.4, 108.9, 105.6, 102.8, 101.2, 56.9, 56.7, 33.5; HRMS (ESI) m/z calcd for C₂₀H₁₆NO₆ (M⁺+H) 366.0978, found 366.0976.

Compound (22): ¹H-NMR (500 MHz, CDCl₃+CF₃CO₂D) δ 8.03 (s, 1H), 7.63 (s, 1H), 7.39-7.36 (m, 2H), 7.33-7.30 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=7.4 Hz, 2H), 6.73 (s, 1H), 6.15 (s, 2H), 5.82 (s, 2H), 3.91 (s, 3H), 3.59 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 192.9, 164.4, 155.1, 154.7, 152.7, 150.5, 149.0, 134.6, 131.5, 130.8, 129.7, 128.5, 127.9, 125.3, 118.3, 110.3, 108.9, 106.2, 102.7, 101.3, 56.6, 56.5, 49.3; HRMS (ESI) m/z calcd for C₂₆H₂₀NO₆ (M⁺+H) 442.1291, found 442.1292.

Compound (23): ¹H-NMR (400 MHz, CDCl₃) δ 8.59 (d, J=7.8 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 6.10 (s, 2H), 4.00 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃+CF₃CO₂D) δ 191.1, 155.5, 152.3, 149.9, 135.1, 132.9, 132.6, 129.9, 128.6, 127.8, 123.3, 122.3, 109.5, 106.5, 106.2, 103.3, 33.1; HRMS (ESI) m/z calcd for C₁₈H₁₂NO₄ (M⁺+H) 306.0766, found 306.0763.

Compound (24): ¹H-NMR (400 MHz, CDCl₃) δ 8.66 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.46-7.42 (m, 1H), 7.38-7.34 (m, 2H), 7.30-7.20 (m, 3H), 7.09 (s, 1H), 6.80 (s, 1H), 6.00 (s, 2H), 5.73 (s, 2H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 191.0, 155.3, 152.3, 149.8, 135.2, 132.8, 132.3, 130.7, 130.0, 128.7, 127.8, 123.4, 122.5, 118.1, 109.6, 106.3, 106.2, 103.1, 47.2; HRMS (ESI) m/z calcd for C₂₄H₁₆NO₄ (M⁺+H) 382.1079, found 382.1079.

Compound (25): ¹H-NMR (400 MHz, CDCl₃) δ 8.62 (d, J=8.5 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.72-7.69 (m, 1H), 7.44-7.41 (m, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 6.18-6.03 (m, 3H), 5.33 (d, J=10.4 Hz, 1H), 5.20-5.11 (m, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 189.5, 163.3, 151.5, 149.3, 134.1, 132.7, 132.3, 131.5, 130.7, 128.8, 126.9, 123.3, 123.0, 117.6, 105.8, 105.6, 103.9, 102.8, 46.3; HRMS (ESI) m/z calcd for C₂₀H₁₄NO₄ (M⁺+H) 322.0923, found 332.0923.

Compound (26): ¹H-NMR (400 MHz, CDCl₃) δ 8.66 (d, J=8.4 Hz, 1H), 8.32 (d, J=7.7 Hz, 1H), 7.73-7.70 (m, 1H), 7.46-7.42 (m, 1H), 7.35 (s, 1H), 7.14 (s, 1H), 6.13 (s, 2H), 4.66 (t, J=5.9 Hz, 2H), 3.87 (t, J=6.2 Hz, 2H), 3.40 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 190.9, 155.4, 152.3, 49.7, 135.2, 132.8, 132.8, 130.1, 128.4, 127.7, 123.4, 109.8, 106.4, 106.1, 103.2, 70.0, 60.0, 45.0; HRMS (ESI) m/z calcd for C₂₀H₁₆NO₅ (M⁺+H) 350.1028, found 350.1026.

Compound (27): ¹H-NMR (400 MHz, CDCl₃) δ 8.48-8.45 (m, 2H), 7.76 (d, J=9.8 Hz, 1H); 7.19 (s, 1H), 7.13 (s, 1H), 6.11 (s, 2H), 4.00 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 190.6, 163.9, 155.7, 152.4, 150.0, 138.1, 132.8, 131.2, 131.1, 130.0, 124.9, 123.7, 121.4, 108.8, 106.6, 106.2, 103.3, 33.2; HRMS (ESI) m/z calcd for C₁₈H₁₁BrNO₄ (M⁺+H) 383.9871, found 383.9866.

Compound (28): ¹H-NMR (400 MHz, CDCl₃) δ 8.51 (d, J=8.8 Hz, 1H); 7.7 (s, 1H), 7.31-7.26 (m, 2H), 7.13 (s, 1H), 7.09 (s, 1H), 6.08 (s, 2H), 3.99 (s, 3H), 3.91 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃+CF₃CO₂D) δ 192.2, 159.3, 153.2, 152.7, 149.6, 133.6, 129.4, 127.3, 126.4, 125.1, 108.2, 106.9, 106.1, 103.3, 55.9, 33.4; HRMS (ESI) m/z calcd for C₁₉H₁₄NO₅ (M⁺+H) 336.0872, found 336.0868.

Compound (29): ¹H-NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.66 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 6.09 (s, 2H), 4.05 (s, 3H), 3.99 (s, 311), 3.99 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃+CF₃CO₂D) δ 191.2, 156.0, 153.8, 152.4, 149.8, 149.6, 133.3, 129.8, 129.2, 116.8, 109.6, 108.0, 106.5, 105.9, 103.2, 103.0, 56.6, 56.3, 33.2; HRMS (ESI) m/z calcd for C₂₀H₁₆NO₆ (M⁺+H) 366.0978, found 366.0978.

Compound (30): ¹H-NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.09 (s, 1H), 6.10 (s, 1H), 4.55-4.48 (m, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.79-3.92 (m, 4H), 2.60-2.48 (in, 6H), 2.06-1.97 (m, 2H); ¹³C-NMR (100 MHz, CDCl₃+CF₃CO₂D) δ 191.2, 152.9, 152.5, 150.1, 150.0, 131.9, 129.6, 129.4, 116.3, 110.4, 107.5, 106.7, 104.8, 103.5, 103.2, 64.2, 56.7, 56.2, 55.5, 52.9, 42.0, 24.3; HRMS (ESI) m/z calcd for C₂₆H₂₇N₂O₇ (M⁺+H) 479.1818, found 479.1820.

Compound (31): ¹H-NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.66 (s, 1H), 7.64-7.59 (m, 1H), 7.19-7.13 (m, 1H), 7.08 (s, 1H), 7.07-7.03 (m, 1H), 6.43 (s, 1H), 6.09 (s, 2H), 4.47 (t, J=6.8 Hz, 2H), 4.22 (t, J=6.8 Hz, 2H), 4.05 (s, 3H), 4.00 (s, 3H), 2.39-2.32 (m, 2H); ¹³C-NMR (100 MHz, CDCl₃+CF₃CO₂D) δ 191.8, 156.5, 153.1, 152.8, 150.1, 135.3, 132.2, 129.8, 129.6, 121.9, 121.0, 116.4, 110.5, 107.7, 107.1, 104.9, 103.6, 103.3, 56.7, 56.3, 47.5, 42.1, 30.3; HRMS (ESI) m/z calcd for C₂₅H₂₂N₃O₆ (M⁺+H) 460.1509, found 460.1507.

Compound (32): ¹H-NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.3 Hz, 1H), 7.69-7.64 (m, 4H), 7.53-7.47 (m, 3H), 7.32-7.28 (m, 1H), 7.06-7.02 (m, 1H), 5.56 (d, J=7.6 Hz, 1H), 3.01 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 189.8, 166.0, 160.7, 151.3, 143.0, 141.0, 138.1, 135.8, 135.6, 135.2, 135.1, 134.8, 132.1, 131.3, 130.5, 129.9, 128.0, 127.7, 127.0, 126.2, 125.3, 118.2, 99.7, 16.0; HRMS (ESI) m/z calcd for C₂₆H₁₇N₂O₂ (M⁺+H) 389.1290, found 389.1288.

Compound (33): ¹H-NMR (400 MHz, CDCl₃) δ 7.94 (d, J=5.2 Hz, 1H), 7.86 (d, J=5.2 Hz, 1H), 7.37-7.22 (m, 7H), 5.81 (s, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ 189.1, 159.5, 156.6, 140.3, 137.7, 136.8, 135.4, 134.9, 133.6, 131.1, 129.4, 128.8, 128.0, 126.0, 123.8, 123.2, 123.0, 110.2, 47.9; HRMS (ESI) m/z calcd for C₂₁H₁₄NO₂S (M⁺+H) 344.0745, found 344.0745.

Compound (34): ¹H-NMR (500 MHz, CDCl₃+CF₃CO₂D) δ 8.74 (d, J=8.1 Hz, 1H), 8.37 (d, J=8.1 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.83-7.80 (m, 1H), 7.59-7.53 (m, 2H), 7.32-7.21 (m, 3H), 7.03-7.00 (m, 1H), 6.96 (d, J=7.4 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 5.65 (s, 2H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 191.5, 164.4, 156.0, 140.2, 136.6, 135.1, 134.7, 134.1, 132.8, 131.5, 129.8, 129.3, 129.0, 128.2, 125.9, 124.0, 123.3, 123.0, 116.0, 113.7, 110.0, 96.7, 54.4; HRMS (ESI) m/z calcd for C₂₃H₁₅INO₂ (M⁺+H) 464.0147, found 464.0151.

Compound (35): ¹H-NMR (400 MHz, CDCl₃) δ 8.75 (d, J=8.1 Hz, 1H), 8.40 (d, J=7.8 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.94-7.86 (m, 3H), 7.82-7.79 (m, 1H), 7.61-7.58 (m, 2H), 7.53-7.49 (m, 1H), 7.04-7.00 (m, 1H), 5.57 (d, J=7.1 Hz, 1H); ¹³C-NMR (125 MHz, CDCl₃+CF₃CO₂D) δ 191.5, 154.6, 146.4, 137.7, 136.7, 135.6, 135.4, 134.4, 133.6, 133.1, 132.1, 131.8, 131.6, 131.2, 129.1, 128.3, 126.8, 124.5, 124.1, 124.0, 123.5, 121.2, 110.2; HRMS (ESI) m/z calcd for C₂₂H₁₃N₂O₄ (M⁺+H) 369.0875, found 369.0876.

Compound (36): ¹H-NMR (400 MHz, CDCl₃) δ 8.67 (d, J=8.1 Hz, 1H), 8.36 (d, J=7.6 Hz, 1H), 7.78-7.65 (m, 4H), 7.53-7.45 (m, 3H), 7.16 (s, 1H), 5.11 (s, 1H), 3.92 (s, 3H), 3.39 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃+CF₃CO₂D) δ 192.6, 155.1, 152.0, 150.6, 136.8, 135.6, 133.4, 131.0, 130.9, 130.7, 129.0, 128.9, 127.9, 127.7, 123.5, 108.4, 107.8, 56.6, 55.9; HRMS (ESI) m/z calcd for C₂₄H₁₈NO₄ (M⁺+H) 384.1236, found 384.1239.

Compound (37): ¹H-NMR (600 MHz, CDCl₃) δ 8.65 (d, J=7.9 Hz, 1H), 8.35 (d, J=7.3 Hz, 1H), 7.77 (d, J=1.4 Hz, 1H), 7.74-7.72 (m, 1H), 7.55 (dd, J=7.7, 1.5 Hz, 1H), 7.50-7.47 (m, 2H), 4.05 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 189.4, 163.5, 155.0, 139.8, 134.2, 133.9, 133.9, 132.1, 128.9, 127.8, 126.4, 124.5, 123.9, 123.8, 109.3, 32.5; HRMS (EST) m/z calcd for C₁₇H₁₁NO₂Br (M⁺+H) 339.9973, found 339.9976.

Compound (38): ¹H-NMR (600 MHz, CDCl₃) δ 8.63 (d, J=8.0 Hz, 1H), 8.34 (d, J=8.1 Hz, 1H), 7.73-7.70 (m, 2H), 7.57 (dd, J=8.0, 1.9 Hz, 1H), 7.51-7.46 (m, 2H), 4.03 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ 189.0, 163.5, 156.0, 137.1, 136.5, 135.6, 134.2, 132.1, 128.9, 127.7, 127.0, 125.8, 124.1, 123.7, 123.7, 108.6, 32.5; HRMS (ESI) m/z calcd for C₁₇H₁₁NO₂Br (M⁺+H) 339.9973, found 339.9976.

Compound (39): ¹H-NMR (400 MHz, CDCl₃+CF₃CO₂D) δ 8.66 (d, J=8.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.61-7.57 (m, 2H), 4.16 (3H); ¹³C-NMR (100 MHz, CDCl₃+CF₃CO₂D) δ 185.0, 165.0, 153.7, 146.3, 139.6, 135.5, 135.3, 131.8, 129.2, 128.8, 125.7, 125.6, 125.1, 124.0, 123.5, 110.6, 33.5; HRMS (ESI) m/z calcd for C₁₇H₁₁N₂O₄ (M⁺+H) 307.0719, found 307.0721.

Compound (40): ¹H-NMR (400 MHz, CDCl₃) δ 8.59 (d, J=8.7 Hz, 1H), 7.92-7.90 (m, 1H), 7.72-7.68 (m, 1H), 7.63-7.61 (m, 1H), 7.52-7.40 (m, 4H), 3.89 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.5, 157.7, 137.8, 134.0, 133.5, 133.4, 131.6, 129.2, 128.1, 127.7, 125.3, 123.5, 122.4, 122.3, 110.0, 33.1.

Compound (4a): ¹H-NMR (400 MHz, CDCl₃+(CD₃)₂SO) δ 8.46 (d, J=8.1 Hz, 1H), 8.13 (d , J=7.9 Hz, 1H), 7.57-7.53 (m, 1H), 7.30-7.27 (m, 2H), 7.08-7.00 (m, 4H), 6.88-6.85 (m, 2H), 5.55 (d, J=7.4 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃1+(CD₃)₂SO) δ 190.4, 162.6, 155.9, 141.0, 136.6, 134.1, 133.8, 132.9, 132.5, 130.9, 130.5, 129.0, 128.3, 126.8, 124.2, 123.8, 123.1, 122.2, 121.9, 120.7, 118.7, 108.2; HRMS (ESI) m/z calcd for C₂₃H₁₄NO₂ (M⁺) 336.1025, found 336.1026.

Compound (5a): ¹H-NMR (400 MHz, CDCl₃) δ 8.56 (d, J=8.0 Hz, 1H), 8.41 (d, J=7.5 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.76-7.71 (m, 3H), 7.64 (d, J=7.0 Hz, 1H), 7.56-7.52 (m, 2H), 7.50-7.46 (m, 2H), 5.46 (s, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ 189.5, 163.0, 137.2, 136.3, 135.7, 135.5, 134.1, 134.0, 132.9, 132.6, 132.2, 131.7, 131.6, 129.9, 129.5, 129.2, 128.6, 127.1, 124.7, 123.8, 122.8, 107.5, 47.9; HRMS (ESI) m/z calcd for C₂₂H₁₃N₂O (M⁺) 321.1028, found 321.1028.

Compound (42): ¹H-NMR (400 MHz, CDCl₃) δ 8.73 (d, J=8.1 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.0 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.45-7.42 (m, 2H), 7.33 (t, J=8.4 Hz, 2H), 7.27-7.23 (m, 1H), 7.05 (t, J=7.6 Hz, 1H), 5.6 (d, J=7.5 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.5, 164.5, 163.6, 162.0, 155.2, 137.0, 134.7, 134.3, 133.4, 133.3, 132.7, 132.6, 130.8, 130.6, 130.5, 128.7, 127.4, 124.0, 123.7, 122.9, 122.2, 117.3 117.1, 108.4; HRMS (ESI) m/z calcd for C₂₂H₁₃NO₂F (M⁺+H) 342.0930, found 342.0932.

Compound (43): ¹H-NMR (400 MHz, CDCl₃) δ 8.71 (d, J=8.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.55 (d, J=7.0 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.27-7.23 (m, 1H), 7.07 (t, J=7.6 Hz, 1H), 5.65 (d, J=7.5 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.5, 163.5, 154.9, 136.9, 136.2, 135.9, 134.6, 134.3, 132.8, 132.7, 130.9, 130.3, 130.1, 128.7, 127.4, 123.9, 123.7, 123.0, 122.2, 108.4; HRMS (ESI) m/z calcd for C₂₂H₁₃NO₂Cl (M⁺+H) 358.0635, found 358.0625.

Compound (44): ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.71 (td, J=8.1, 1.1 Hz, 1H), 7.61 (d, J=6.7 Hz, 1H), 7.45 (td, J=7.3, 1.2 Hz, 3H), 7.39 (qd, J=14.22, 1.5 Hz, 1H), 4.49 (t, J=8.0 Hz, 2H), 1.94-1.86 (m, 2H), 1.56-1.40 (m, 4H), 0.96 (t, J=7.1 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.4, 163.3, 155.6, 137.2, 135.3, 133.8, 133.2, 132.3, 131.0, 128.4, 127.1, 123.5, 123.2, 122.3, 108.5, 44.7, 29.1, 29.0, 22.4, 14.0; HRMS (ESI) m/z calcd for C₂₁H₂₀NO₂(M⁺+H) 318.1494, found 318.1495.

Compound (45): ¹H-NMR (400 MHz, CDCl₃) δ 8.66 (d, J=8.1 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.69 (td, J=8.3, 1.3 Hz, 1H), 7.61-7.57 (m, 1H), 7.44 (td, J=8.2, 1.1 Hz, 1H), 7.37-7.26 (m, 6H), 7.21-7.17 (m, 2H), 4.49 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.1 Hz, 2H), 1.97-1.82 (m, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.4, 163.4, 141.6, 137.1, 135.2, 133.8, 133.2, 132.3, 130.9, 128.5, 128.4, 127.2, 126.0, 123.5, 123.2, 122.2, 108.5, 44.5, 35.3, 28.9, 28.4; HRMS (ESI) m/z calcd for C₂₆H₂₂NO₂ (M⁺+H) 380.1651, found 380.1656.

Compound (46): ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (d, J=8.2 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.72 (td, J=8.2, 1.2 Hz, 1H), 7.61 (d, J=7.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.38 (t, J=7.3 Hz, 1H), 4.66-4.62 (m, 2H), 3.61 (t, J=5.53 Hz, 2H), 3.42 (s, 3H), 2.21-2.14 (m, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ 190.6, 163.5, 155.8, 137.0, 135.2, 133.8, 133.4, 132.4, 130.9, 128.3, 127.1, 123.5, 123.4, 123.3, 123.2, 108.5. 70.1, 59.0, 42.9, 29.5; HRMS (ESI) m/z calcd for C₂₀H₁₈NO₃ (M⁺+H) 320.1287, found 320.1287.

The aforesaid data shows that the method of the present disclosure can be used to prepare clinical used indenoisoquinoline derivatives in a mild condition rapidly and effectively. For example, Compound (29) prepared in the present disclosure is a clinical used drug NSC314622, Compound (30) is a clinical used drug LMP-400, and Compound (31) is a clinical used drug LMP-776. In the method of the present disclosure, only a little amount of Cu-containing catalyst is used to obtain the indenoisoquinoline derivatives. In addition, when water is used as a solvent in the method of the present disclosure, the use of organic solvents can be prevented to reduce the environmental pollution.

Although the present disclosure has been explained in relation to its embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the disclosure as hereinafter claimed. 

1. A method for preparing indenoisoquinoline derivatives represented by one of the following formulas (1) to (31), (34) to (39) and (41) to (46), comprising the following steps:

(A) providing a first reactant represented by the following formula (II) and a second reactant represented by the following formula (III):

wherein A is —OH or —NHR₂; X is —CO; Y ring is a phenyl ring; Z is F, Cl, Br or I; n is an integral of 1 to 4; each R₁ independently is H, nitro, Br, Cl or methoxy; or when n is 2, two adjacent R₁ and carbon atoms attached thereto together form a dioxolane; and R₂ is H, methyl, ethyl, propyl, pentyl, allyl, phenyl, benzyl, morpholinoethyl, morpholinopropyl, imidazolpropyl, methoxyethyl, methoxypropyl, methoxybutyl, fluorophenyl, chlorophenyl,

wherein * is a bonding position,

wherein m is an integral of 1 to 4; and each R₃ independently is H, Br, nitro, or methoxy; or when m is 2, two adjacent R₃ and carbon atoms attached thereto together form a dioxolane; and (B) reacting the first reactant represented by the formula (II) and the second reactant represented by the formula (III) in a solvent with a catalyst and adding R₂NH₂ therein in the case where A is —OH, to obtain the indenoisoquinoline derivatives represented by one of the following formulas (1) to (31), (34) to (39) and (41) to (46), wherein the catalyst comprises Cu⁺ or Cu²⁺.
 2. The method of claim 1, wherein the solvent is water, MeCN, DMF, DMSO, dioxane, toluene, or a combination thereof.
 3. (canceled)
 4. The method of claim, wherein the catalyst is selected from the group consisting of CuI, CuSO₄, CuCl, CuCl₂, and a hydrate thereof.
 5. The method of claim 1, wherein an alkali is further added in the step (B).
 6. The method of claim 5, wherein the alkali is selected from the group consisting of K₂CO₃, Na₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, CsOH, Li₃PO₄, Na₃PO₄, K₃PO₄ and Cs₃PO₄.
 7. (canceled)
 8. The method of claim 1, wherein Z in the formula (II) is I.
 9. (canceled)
 10. The method of claim, wherein the formula (II) is one of the following formulas (II-4) to (II-6):


11. (canceled)
 12. The method of claim 1, wherein the formula (III) is one of the following formulas (III-1) to (III-4):


13. The method of claim 1, wherein the step (B) comprises the following steps in the case where A is —OH: (B1) reacting the first reactant represented by the formula (II) and the second reactant represented by the formula (III) in the solvent with the catalyst to obtain an intermediate represented by the following formula (IV), wherein the catalyst comprises Cu⁺ or Cu²⁺:

and (B2) reacting the intermediate represented by the formula (IV) with R₂NH₂ to obtain the indenoisoquinoline derivatives represented by one of the following formulas (1) to (31), (34) to (39) and (41) to (46).
 14. (canceled)
 15. The method of claim, wherein the catalyst is selected from the group consisting of CuI, CuSO₄, CuCl, CuCl₁₂, and a hydrate thereof.
 16. The method of claim 13, wherein an alkali is further added in the step (B1).
 17. The method of claim 16, wherein the alkali is selected from the group consisting of K₂CO₃, Na₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, CsOH, Li₃PO₄, Na₃PO₄, K₃PO₄ and Cs₃PO₄.
 18. The method of claim 13, wherein an acid is further added in the step (B2).
 19. The method of claim 18, wherein the acid is camphorsulfonic acid. 20-22. (canceled) 